(R)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-naphthalenemethane amine (“CNC-base,” “cinacalcet base,” or “cinacalcet”) has the following formula:
and a CAS number of 226256-56-0. This molecule is the free base form of cinacalcet hydrochloride, C22H22F3N.HCl. Cinacalcet hydrochloride (“CNC—HCl”), has a molecular weight of 393.9 and CAS number 364782-34-3. CNC—HCl is marketed as SENSIPAR™, and is the first drug in a class of compounds known as calcimimetics to be approved by the FDA.
Calcimimetics are a class of orally active, small molecules that decrease the secretion of parathyroid hormone (“PTH”) by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH, an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.
CNC—HCl is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with CNC—HCl lowers serum levels of PTH as well as the calcium/phosphorus ion product, a measure of the amount of calcium and phosphorus in the blood.
U.S. Pat. No. 6,011,068 discloses calcium receptor-active molecules, such as those having the general structure of cinacalcet. U.S. Pat. No. 6,211,244 (“'244 patent”) discloses calcium receptor-active compounds related to cinacalcet and methods of preparing such compounds. Using the methods disclosed in the '244 patent, as well as DRUGS OF THE FUTURE (2002) 27(9):831, the desired cinacalcet enantiomer, may be produced by reacting 3-[3-(trifluoromethyl)phenyl]propylamine with 1-acetyl naphthalene in the presence of titanium (IV) isopropoxide, to produce an imine corresponding to cinacalcet, followed by treatment with ethanolic or methanolic sodium cyanoborohydride, and resolution of the racemic cinacalcet by chiral liquid chromatography, as depicted in the following scheme:
However, this process involved the use of flammable and highly toxic reagents, such as titanium (IV) isopropoxide and ethanolic or methanolic sodium cyanoborohydride.
In another process disclosed in the '244 patent, cinacalcet may be produced by treating 3-trifluoromethylcinnamonitrile with diisobutyl aluminum hydride, followed by treatment of the intermediate aluminum-imine complex with (R)-1-(1-naphthyl)ethylamine, and reduction of the intermediate imine with ethanolic sodium cyanoborohydride, according to the following scheme:
Synthesis of the 3-trifluoromethylcinnamonitrile precursor in this process is disclosed only in Tetrahedron Letters (2004) 45:8355. Although this is a possible process, Al[iBu] is highly flammable and, thus, this process is not ideal.
Similarly, using the process disclosed in the '244 patent, as well as DRUGS OF THE FUTURE (2002) 27 (9): 831, the desired cinacalcet enantiomer may be produced by reacting (R)-1-(1-naphthyl)ethylamine with 3-[3-(trifluoromethyl)phenyl]propionaldehyde in the presence of titanium (IV) isopropoxide to produce the imine that corresponds to cinacalcet, followed by treatment with ethanolic sodium cyanoborohydride, according to the following scheme:

However, the processes mentioned require the use of reagents such as titanium (IV) isopropoxide and ethanolic sodium cyanoborohydride, which are highly flammable, difficult to handle and toxic. Moreover, the only synthetic route known to the precursor of CNC-base, 3-[3-(trifluoromethyl)phenyl]propionaldehyde is disclosed in Tetrahedron Letters (2004) 45: 8355, and is described in the following scheme:
by reduction of the double bond of the corresponding cinnamic acid derivative, followed by reduction of the carboxylic acid moiety to the corresponding alcohol, which is then oxidized to the aldehyde by Swern-oxidation, using reagents which are not environmentally friendly reagents and are unstable, such as oxalyl chloride and dimethyl sulfoxide.
Thus, there is a need in the art for an improved process for the preparation of CNC-base and salts thereof, preferably, the hydrochloride salt, that is more environmentally friendly. The present invention provides such an alternative.